US4325950A - Platinum caffeine chloride anion complex and method - Google Patents
Platinum caffeine chloride anion complex and method Download PDFInfo
- Publication number
- US4325950A US4325950A US06/122,144 US12214480A US4325950A US 4325950 A US4325950 A US 4325950A US 12214480 A US12214480 A US 12214480A US 4325950 A US4325950 A US 4325950A
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- US
- United States
- Prior art keywords
- caffeine
- complex
- platinum
- administered
- compound
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine
Definitions
- This application relates to formation of a platinum-amino complex and particularly to the formation of a platinum[caffeine] Cl 3 complex anion. Particularly, this application relates to the treatment of cancer with this complex.
- cis Pt(NH 3 ) 2 Cl 2 The anti-cancer activity of cis Pt(NH 3 ) 2 Cl 2 is well documented and, is believed to result not from prevention of DNA replication but from damage to the DNA producing faulty replication. Damaged DNA is repaired by various DNA repair enzymes. It thus follows that if an agent such as cis Pt(NH 3 ) 2 Cl 2 which damages DNA is administered along with another agent which inhibits a DNA repair enzyme, then the kill of cancerous cells will be greatly enhanced.
- Caffeine is an inhibitor of DNA repair and it has been shown in cell culture studies that caffeine greatly increases cell kill caused by cis Pt(NH 3 ) 2 Cl 2 . While these cell culture studies have been demonstrably successful in vitro, they have not been successfully replicated in vivo, i.e., no enhancement of anti-cancer activity occurs when these compounds are combined.
- an anionic, heavy metal-containing caffeine complex can be prepared by reacting caffeine with K 2 PtCl 4 . This reaction is carried out at essentially a neutral pH, i.e., between 6 and 8, and at ambient temperatures and pressures for several days.
- the product is an easily dissociated potassium salt of Pt(caffeine)Cl 3 .
- the caffeine complex differs from all other known compounds of Pt which have anti-cancer activity in several aspects.
- all analogues of cis Pt(NH 3 ) 2 Cl 2 contain two saturated amines in cis positions. These amines may be part of a chelate. These compounds also contain either two anions or a bidentate chelating ion with a -2 charge which always produce Pt complexes which are uncharged.
- the complex formed with caffeine contrarily, has a -1 charge, contains three anions bound to Pt and, perhaps most importantly, has no possibility for cis and trans isomers. It is thus highly likely that the complex of this invention acts by an entirely different mechanism than previously known Pt-containing anti-tumor agents.
- the complex of the subject invention was prepared by combining a 1:1 molar ratio of caffeine with K 2 PtCl 4 in aqueous solution under conditions of ambient temperature and pressure for a period of several days.
- the solution was concentrated by evaporation and filtered utilizing filter paper and a mild vacuum.
- the resultant precipitate was a highly soluble yellow-orange powder.
- the complex was then injected intraperitoneally to white mice according to the standards set forth in the P388 Lymphocytic Leukemia Test System used by the National Cancer Institute. All of the test conditions used in this example parallel those of that test. When compared with the control, the life span of the treated mice was increased from 10 days to from 15 to 24 days.
- composition of the invention is administered orally, intraperitoneally, intravenously, or intramuscularly.
- composition is used in combination with other drugs. This latter composition increased the life span from 17 to 20 days.
- composition of this invention reacts in ways currently unknown but apparently not identical to previous mechanisms, the complex of the subject invention may be used in combination with other anti-cancer drugs to further enhance the anti-cancer activity of the particular treatment.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A platinum caffeine chloride anionic complex is formed by reacting K2PtCl4 with caffeine in an aqueous solution at neutral pH under ambient conditions of temperature and pressure. This complex is particularly useful for cancer treatment.
Description
This application relates to formation of a platinum-amino complex and particularly to the formation of a platinum[caffeine] Cl3 complex anion. Particularly, this application relates to the treatment of cancer with this complex.
The anti-cancer activity of cis Pt(NH3)2 Cl2 is well documented and, is believed to result not from prevention of DNA replication but from damage to the DNA producing faulty replication. Damaged DNA is repaired by various DNA repair enzymes. It thus follows that if an agent such as cis Pt(NH3)2 Cl2 which damages DNA is administered along with another agent which inhibits a DNA repair enzyme, then the kill of cancerous cells will be greatly enhanced.
Caffeine is an inhibitor of DNA repair and it has been shown in cell culture studies that caffeine greatly increases cell kill caused by cis Pt(NH3)2 Cl2. While these cell culture studies have been demonstrably successful in vitro, they have not been successfully replicated in vivo, i.e., no enhancement of anti-cancer activity occurs when these compounds are combined.
Relevant references describing the effect of the Pt(NH3)2 Cl2 and caffeine are:
______________________________________
Author Title Number
______________________________________
Van Den Berg,
Synergism Between the Anti-
75-4316
H. W. tumor Agent cis Platinum (II)
Diamminedichloride and
Caffeine: Toxicological and
Molecular Studies (abstract)
Van Den Berg,
Post-Republican Repair of
76-4670
H. W. DNA in Chinese Hamster Cells
Treated with Cis Platinum (II)
Diamine Dichloride, Enhancement
of Toxicity and Chromosome
Damage by Caffeine
______________________________________
It was theorized that the difference between in vivo and in vitro reactions may have been due to solubility and membrane transport properties and that, if the caffeine molecule could be complexed in such a way that these properties would be enhanced, the successful anti-cancer composition could be produced.
It has now been discovered that an anionic, heavy metal-containing caffeine complex can be prepared by reacting caffeine with K2 PtCl4. This reaction is carried out at essentially a neutral pH, i.e., between 6 and 8, and at ambient temperatures and pressures for several days. The product is an easily dissociated potassium salt of Pt(caffeine)Cl3.
The caffeine complex differs from all other known compounds of Pt which have anti-cancer activity in several aspects. First, all analogues of cis Pt(NH3)2 Cl2 contain two saturated amines in cis positions. These amines may be part of a chelate. These compounds also contain either two anions or a bidentate chelating ion with a -2 charge which always produce Pt complexes which are uncharged. The complex formed with caffeine, contrarily, has a -1 charge, contains three anions bound to Pt and, perhaps most importantly, has no possibility for cis and trans isomers. It is thus highly likely that the complex of this invention acts by an entirely different mechanism than previously known Pt-containing anti-tumor agents.
The complex of the subject invention was prepared by combining a 1:1 molar ratio of caffeine with K2 PtCl4 in aqueous solution under conditions of ambient temperature and pressure for a period of several days. The solution was concentrated by evaporation and filtered utilizing filter paper and a mild vacuum. The resultant precipitate was a highly soluble yellow-orange powder.
The complex was then injected intraperitoneally to white mice according to the standards set forth in the P388 Lymphocytic Leukemia Test System used by the National Cancer Institute. All of the test conditions used in this example parallel those of that test. When compared with the control, the life span of the treated mice was increased from 10 days to from 15 to 24 days.
These values compare favorably with those obtained elsewhere utilizing the same cancer and cancer test procedure and the common cancer drug cis Pt(NH3)2 Cl2. As examples, the composition of the invention is administered orally, intraperitoneally, intravenously, or intramuscularly. In further examples the composition is used in combination with other drugs. This latter composition increased the life span from 17 to 20 days.
It is apparent, therefore, that the complex of this invention is at least equal to and may actually be superior to a known cancer-fighting drug.
It is also apparent that, because the composition of this invention reacts in ways currently unknown but apparently not identical to previous mechanisms, the complex of the subject invention may be used in combination with other anti-cancer drugs to further enhance the anti-cancer activity of the particular treatment.
Claims (9)
1. The complex comprising the potassium salt of Pt[caffeine] Cl3.
2. A method for preparing Pt[caffeine] Cl3 compound comprising reacting K2 PtCl4 with caffeine in an aqueous solution while maintaining pH near neutrality under time-temperature conditions sufficient to form Pt[caffeine] Cl3 and potassium chloride.
3. A method for treating P388 Lymphocylic Leukemia in mice comprising administering an effective amount of the potassium salt of Pt[caffeine] Cl3 to a leukemic subject.
4. The method of claim 3 in which the potassium salt of Pt[caffeine] Cl3 is administered in combination with another anticancer agent.
5. A composition for treating P388 Lymphocylic Leukemia in mice comprising the potassium salt of Pt[caffeine] CL3 and a carrier.
6. The method of claim 3 wherein the composition is administered orally.
7. The method of claim 3 wherein the compound is administered intraperitoneally.
8. The method of claim 3 wherein the compound is administered intravenously.
9. The method of claim 3 wherein the compound is administered intramuscularly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/122,144 US4325950A (en) | 1980-02-19 | 1980-02-19 | Platinum caffeine chloride anion complex and method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/122,144 US4325950A (en) | 1980-02-19 | 1980-02-19 | Platinum caffeine chloride anion complex and method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4325950A true US4325950A (en) | 1982-04-20 |
Family
ID=22400934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/122,144 Expired - Lifetime US4325950A (en) | 1980-02-19 | 1980-02-19 | Platinum caffeine chloride anion complex and method |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US4325950A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060241186A1 (en) * | 1999-08-13 | 2006-10-26 | Gerson Stanton L | Alkylating agent combinations in the treatment of cancer |
| EP2266607A2 (en) | 1999-10-01 | 2010-12-29 | Immunogen, Inc. | Immunoconjugates for treating cancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169846A (en) * | 1976-09-06 | 1979-10-02 | Kenji Inagaki | Cis-platinum (ii) complex of trans-l-1,2-diaminocyclohexane |
-
1980
- 1980-02-19 US US06/122,144 patent/US4325950A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169846A (en) * | 1976-09-06 | 1979-10-02 | Kenji Inagaki | Cis-platinum (ii) complex of trans-l-1,2-diaminocyclohexane |
Non-Patent Citations (1)
| Title |
|---|
| Connors et al., Platinum Coordination Complexes in Cancer Chemotherapy, Springer-Verlag, N.Y, pp. 21, 23, 46-52, 64, 65 (1974). * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060241186A1 (en) * | 1999-08-13 | 2006-10-26 | Gerson Stanton L | Alkylating agent combinations in the treatment of cancer |
| US8324282B2 (en) * | 1999-08-13 | 2012-12-04 | Case Western Reserve University | Alkylating agent combinations in the treatment of cancer |
| US8716346B2 (en) | 1999-08-13 | 2014-05-06 | Case Western Reserve University | Alkylating agent combinations in the treatment of cancer |
| EP2266607A2 (en) | 1999-10-01 | 2010-12-29 | Immunogen, Inc. | Immunoconjugates for treating cancer |
| EP2289549A2 (en) | 1999-10-01 | 2011-03-02 | Immunogen, Inc. | Immunoconjugates for treating cancer |
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